Is There a Low-level Copper-toxicity Syndrome?

by Alan R. Gaby, M.D.

In 1983, a practitioner in Vancouver, British Columbia, described a syndrome that was purported to be due to chronic copper toxicity. Symptoms varied but included one or more of the following: rapid thought patterns, insomnia, depression, memory loss, hallucinations, paranoia, and occasionally obsessive-compulsive disorder. The diagnosis of copper overload was based on an elevated hair copper concentration, increased 24-hour urinary copper excretion following a challenge with penicillamine (a copper-chelating agent), and symptomatic improvement after a course of penicillamine therapy.[1] Other investigators have reported that some patients with schizophrenia, depression, autism, tardive dyskinesia, or memory loss have elevated serum copper levels.[2] Because of these observations, some practitioners recommend that patients with various neuropsychiatric symptoms avoid copper supplements, and a number of nutritional supplement companies offer copper-free multivitamin-multimineral products.

Weaknesses of the copper-toxicity theory

The concept that chronic low-level copper toxicity is a cause of neuropsychiatric symptoms has a number of important weaknesses. First, the elevated hair and post-penicillamine-challenge urinary copper levels observed in Vancouver may have been nonspecific findings related to the relatively high copper content of the tap water in this region. Water copper concentrations in Vancouver are frequently greater than 1 mg/L, presumably because of the use of copper pipes. The Vancouver practitioner noted that more than 50% of the patients in his practice had elevated hair copper levels. Copper present in water is known to bind to hair when the hair is washed. The high hair copper levels may have been due primarily to such binding, and may not have been indicative of a high body burden of copper.

Second, in addition to chelating copper, penicillamine chelates mercury and lead and removes them from the body. Both mercury and lead have been implicated as causative factors in neuropsychiatric illness. Therefore, the symptomatic improvement seen after a course of penicillamine therapy may not have been due to the removal of copper.

Third, serum copper levels rise in response to inflammation, and elevated serum copper levels (as seen in the neuropsychiatric conditions mentioned above) are usually not indicative of copper toxicity. Thus, the evidence supporting the existence of a syndrome of chronic low-level copper toxicity is currently unconvincing.

Does low-level copper toxicity cause Alzheimer’s disease?

Some researchers have hypothesized that excessive copper intake could increase the risk of developing Alzheimer’s disease.[3] This hypothesis is based in part on studies in rabbits, dogs, and mice, in which the addition of a small amount of copper (0.12 mg/L) to distilled drinking water resulted in the accumulation of amyloid beta protein in the brain.[4] [5] Amyloid beta protein is thought to be involved in the pathogenesis of Alzheimer’s disease.

In contrast to these findings, copper supplementation prevented premature death in transgenic APP23 mice, which are genetically programmed to overproduce amyloid beta precursor protein.[6] That study suggests that copper might decrease, rather than increase, the risk of developing Alzheimer’s disease. In a double-blind trial, supplementation with 8 mg per day of copper for 12 months had no significant effect on cognitive function, compared with placebo, in patients with mild Alzheimer’s disease, and there was no trend suggesting an adverse effect of copper.[7]

In a more recent study,[8] the concentrations of 8 essential minerals were measured postmortem in 7 brain regions of 9 people with Alzheimer’s disease and 13 controls who had no evidence of brain disease. In the Alzheimer’s cases, for the 7 minerals other than copper, abnormalities were seen in only a few regions of the brain. In those regions, some of the mineral levels were higher and some were lower than those of controls. In contrast, copper levels were decreased in all Alzheimer’s-related brain regions, to about 50-70% of the levels seen in the controls. These low copper concentrations were similar to those seen in Menkes’ disease, which is a genetic disorder in which brain-copper deficiency is the accepted cause of severe brain damage.

Thus, there is at present no convincing evidence that limiting copper intake would be useful for preventing or treating Alzheimer’s disease.

Dietary copper intake has decreased

The copper content of many modern diets may be substantially lower than that of diets consumed in the past. The average copper content of fruits and vegetables declined by 81% between the years 1940 and 2000,[9] presumably because of changes in farming methods that decreased the availability of copper in the soil.[10] In addition, 68% of the copper is lost when whole wheat flour is refined to white flour.[11] Nearly one-third of the diets consumed in the United States, Canada, and England provide less than 1 mg of copper per day.[12] One study found that copper intake of adults ranged from 0.58 mg to 2.03 mg per day.[13] Thus, a substantial minority of people may be failing to meet the Recommended Dietary Allowance for copper (0.9 mg per day for adults).

Importance of copper

Copper is an essential cofactor for many enzymes, and there is evidence that inadequate copper intake can promote the development of cardiovascular disease, glucose intolerance, osteoporosis, and other chronic illnesses.[14] Because the copper content of the typical Western diet appears to be lower than it was in the past, and because the evidence supporting the existence of a syndrome of chronic low-level copper toxicity is unconvincing, it has been my practice not to recommend copper-free multivitamin-multimineral products in most cases. However, the use of copper-free products would seem to be appropriate for people who drink tap water that contains large amounts of copper, as would be suggested by the presence of light-blue stains in the sink or bathtub.

Good food sources of copper include fish, meat, poultry, eggs, nuts, legumes, whole grains, vegetables, and fruits. About two-thirds of the copper is lost when whole wheat flour is refined to white flour.

[1] Nolan KR. Copper toxicity syndrome. J Orthomolec Psychiatry. 1983;12:270-282.

[2] Pfeiffer CC, Mailloux R. Excess copper as a factor in human diseases. J Orthomolec Med. 1987;2:171-182.

[3] Brewer GJ. Copper excess, zinc deficiency, and cognition loss in Alzheimer’s disease. Biofactors. 2012;38:107-113.

[4] Sparks DL, Schreurs BG. Trace amounts of copper in water induce beta-amyloid plaques and learning deficits in a rabbit model of Alzheimer’s disease. Proc Natl Acad Sci. 2003;100:11065-11069.

[5] Sparks DL, et al. Trace copper levels in the drinking water, but not zinc or aluminum influence CNS Alzheimer-like pathology. J Nutr Health Aging. 2006;10:247-254.

[6] Bayer TA, et al. Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Abeta production in APP23 transgenic mice. Proc Natl Acad Sci. 2003;100:14187-14192.

[7] Kessler H, et al. Intake of copper has no effect on cognition in patients with mild Alzheimer’s disease: a pilot phase 2 clinical trial. J Neural Transm. 2008;115:1181-1187.

[8] Xu J, et al. Evidence for widespread, severe brain copper deficiency in Alzheimer’s dementia. Metallomics. 2017;9:1106-1119.

[9] Worthington V. Nutritional quality of organic versus conventional fruits, vegetables, and grains. J Altern Complement Med. 2001;7:161-173.

[10] Miller L, Mitchell HS. Correlation of copper and manganese content of plants and mineral additions to the soil. J Am Diet Assoc. 1931-2;7:252-257.

[11] Schroeder HA. Losses of vitamins and trace minerals resulting from processing and preservation of foods. Am J Clin Nutr. 1971;24:562-573.

[12] Baker DH. Cupric oxide should not be used as a copper supplement for either animals or humans. J Nutr. 1999;129:2278-2279.

[13] Wolf WR, et al. Daily intake of zinc and copper from self selected diets. Fed Proc. 1977;36:1175.

[14] Gaby AR. Copper. In Gaby AR. Nutritional Medicine, 2nd Edition. Concord, NH, 2017,, chapter 32.